Maintenance of the structure of the eukaryotic genome involves a series of proteins such as, but not exclusively, enzymes which not only monitor DNA for alterations but also effect repairs to any alterations with a view to maintaining the integrity of the DNA for the purpose of subsequent meiosis or mitosis.
Different agents cause different types of DNA damage and, as a result, a different series of proteins have evolved in order to repair the different types of damage.
It follows that DNA repair is one of the fundamental processes involved in DNA metabolism and defects in any of the DNA repair mechanisms have major biological consequences, including a significant impact on the well-being of the relevant organism.
A main goal since the discovery of the structure of DNA has been to systematically determine the precise molecular mechanisms that mediate DNA function.
As improved technologies allow for increasingly high resolution studies of DNA it is becomingly increasingly possible to undertake location analysis of DNA, i.e. analysis that enables the precise location of a given event to be determined within the eukaryotic genome. When one considers that the human cell contains 2 metres of DNA packed within chromatin and that these 2 metres of DNA comprise more than 30,000 genes or 3.2 billion base pairs but one is, nevertheless, able to pinpoint the precise location of a given event (within a 100 base pair degree of accuracy) then one begins to appreciate that location analysis is an important tool in understanding events that take place within the genome.
There are a number of agents within the environment which are thought to damage DNA. These agents are both chemical and physical and so comprise genotoxic molecules, typically, man-made, and also physical forces such as electromagnetic radiation such as UV rays and X-rays.
UV rays are known to be particularly damaging to humans and are the commonest cause of skin cancer due to epidermal absorption of ultraviolet radiation. For cancer DNA is believed to be the primary target and it has been shown that photochemical reactions involving DNA have been linked to mutagenesis, carcinogenesis and cell death. Damage caused by UV exposure is characterised by the formation of pyrimidine dimers and in particular thymine dimers. Nature has responded by producing an enzyme, photolyase, which reactivates DNA by the direct repair of thymine dimers. It binds to the damaged DNA and by absorbing energy restores the pyrimidine dimers to their former monomeric state. This repair mechanism is found in many forms of eukaryotic life.
In an analogous fashion other DNA repair proteins, and in particular enzymes, have evolved to repair other forms of DNA damage. Examples of such enzymes include base excision repair enzymes; enzymes which are responsible for direct reversal of damage, repair of DNA-protein crosslinks, mismatch excision repair, nucleotide excision repair, homologous recombination, non-homologous end joining or modulation of nucleotide pools; DNA polymerases, editing and processing nucleases, also gene products which interfere with the Rad6 pathway or which affect chromatin structure, enzymes or gene products encoded by genes which are defective in diseases associated with sensitivity to DNA damaging agents etc. Table 1 lists examples of genes encoding these enzymes and other proteins 1 along with an indication of their functionality and so the nature of the damage that they repair. Many of these enzymes are highly conserved and so homologues exist in different species.
TABLE 1Genes Encoding DNA Repair Enzymes or having a DNA Repair functionGene NameChromosomeNCBI(Synonyms)ActivityLocationAccession No.Base excision repairDNA glycosylases: majoraltered base releasedUNGU12q24.11NM 080911SMUG1U12q13.13NM 014311MBD4U or T opposite G at CpG3q21.3NM 003925sequencesTDGU, T or ethenoC opposite12q23.3NM 003211GOGG18-oxoG opposite C3p25.3NM 016821MUTYH (MYH)A opposite 8-oxoG1p34.1NM 012222NTHL1 (NTH1)Ring-saturated or16p13.3NM 002528fragmented pyrimidinesMPG3-MeA, ethenoA,16p13.3NM 002434hypoxanthineNEIL1Removes thymine glycol15q24.2NM 024608NEIL2Romoves oxidative8p23.1NM 145043products of pyrimidinesOther BER FactorsAPEX1AP endonuclease14q11.2NM 001641APEX2AP endonucleaseXp11.21NM 014481LIG3DNA Ligase17q12NM 013975XRCC1Ligase accessory factor19q13.31NM 006297PNKPConverts some DNA19q13.33NM 007254breaks to ligatable endsPoly (ADP-ribose)polymerase (PARP)enzymesPARP1 (ADPRT)Protects strand1q42.12NM 001618interruptionsPARP2 (ADPRTL2)PARP-like enzyme14q11.2NM 005484Direct Reversal ofDamageMGMTO6-meG alkyltransferase10q26.3NM 002412MGC90512 (ABH2)1-meA dioxygenase12q24.11NM 001655DEPC-1 (ABH3)1-meA dioxygenase11p11.2NM 139178Repair of DNA-protein cross linksTDP1Removes covalently14q32.11NM 018319bound TOP1-DNAcomplexesMismatch excisionrepair (MMR)MSH2Mismatch and loop2p21NM 000251recognitionMSH3Mismatch and loop5q14.1NM 002439recognitionMSH6Mismatch and loop2p16.3NM 000179recognitionMSH4MutS homologues1p31.1NM 002440specialised for meiosisMSH5MutS homologues6p21.33NM 002441specialised for meiosisPMS1MutL homologue2q32.2NM 000534MLH1MutL homologues3p22.3NM 000249forming heterodimerPMS2MutL homologues7p22.1NM 000535forming heterodimerMLH3MutL homologues of14q24.3NM 014381unknown functionPMS2L3MutL homologues of7q11.23D38437unknown functionPMS2L4 (PMS6)MutL homologues of7q11.21D38500unknown functionNucleotide excision(XP = xerodermarepair (NER)pigmentosum)XPCBinds damaged DNA as3p25.1NM 04628complexRAD23B (HR23B)Binds damaged DNA as9q31.2NM 002874complexCETN2Binds damaged DNA asXq28NM 004344complexRAD23A (HR23A)Substitutes for HR23B19p13.13NM 005053XPABinds damaged DNA in9q22.33NM 000380preincision complexRPA1Binds DNA in preincision17p13.3NM 002945complexRPA2Binds DNA in preincision1p35.3NM 002946complexRPA3Binds DNA in preincision7p21.3NM 002947complexTF11HCatalyses unwinding inpreincision complexERCC3 (XPB)3′ to 5′ DNA helicase2q14.3NM 000122ERCC2 (XPD)5′ to 3′ DNA helicase19q13.32NM 000400GTF2H1Core TFIIH subunit p6211p15.1NM 005316GTF2H2Core TFIIH subunit p445q13.2NM 001515GTF2H3Core TFIIH subunit p3412q24.31NM 001516GTF2H4Core TFIIH subunit p526p21.33NM 001517GTF2H5 (TTDA)Core TFIIH subunit p86p25.3NM 207118CDK7Kinase subunit of TFIIH5q13.2NM 001799CCNHKinase subunit of TFIIH5q14.3NM 001239MNAT1Kinase subunit of TFIIH14q23.1NM 002431ERCC5 (XPG)3′ incision13q33.1NM 000123ERCC15′incision subunit19q13.32NM 001983ERCC4 (XPF)5′incision subunit16p13.12NM 005236LIG1DNA joining19q13.32NM 000234NER-relatedCKN1 (CSA)Cockayne syndrome;5q12.1NM 000082needed for transcription-coupled NERERCC6 (CSB)Cockayne syndrome;10q11.23NM 000124needed for transcription-coupled NERXAB2 (HCNP)Cockayne syndrome;19p13.2NM 020196needed for transcription-coupled NERDDB1Complex defective in XP11q12.2NM 001923group EDDB2Complex defective in XP11p11.2NM 000107group EMMS19L (MMS19)Transcription and NER10q24.1NM 022362HomologousRecombinationRAD51Homologous pairing15q15.1NM 002875RAD51L1 (RAD51B)Rad51 homologue14q24.1NM 002877RAD51CRad51 homologue17q23.2NM 002876RAD51L3 (RAD51D)Rad51 homologue17q12NM 002878DMC1Rad51 homologue,22q13.1NM 007068meiosisXRCC2DNA break and crosslink7q36.1NM 005431repairXRCC3DNA break and crosslink14q32.33NM 005432repairRAD52Accessory factors for12p13.33NM 002879recombinationRAD54LAccessory factors for1p34.1NM 003579recombinationRAD54BAccessory factors for8q22.1NM 012415recombinationBRCA1Accessory factor for17q21.31NM 007295transcription andrecombination, E3Ubiquitin ligaseBRCA2 (FANCD1)Cooperation with RAD5113q13.1NM 000059essential functionSHFM1 (DSS1)BRCA2 associated7q21.3NM 006304RAD50ATPase in complex with5q23.3NM 005732MRE11A, NBS1MRE11A3′exonuclease11q21NM 005590NBS1Mutated in Nijmegen8q21.3NM 002485breakage syndromeMUS81A structure specific DNA11q13.1NM 025128nucleaseEME1 (MMS4L)A structure specific DNA17q21.33NM 152463nucleaseEME2Essenital meiotic16p13.3NM 0010865endonuclease 1homologue 2Non-homologousend-joiningG22P1 (Ku70)DNA end binding22q13.2NM 001469XRCC5 (Ku80)DNA end binding2q35NM 021141PRKDCDNA-dependent protein8q11.21NM 006904kinase catalytic subunitLIG4Ligase13q33.3NM 002312XRCC4Ligase accessory factor5q14.2NM 003401DCLRE1C (Artemis)Nuclease10p13NM 022487XLF (Cernunnos,XRCC4-LIG4 interacting2q35NM 024782NHEJ1)factorModulation ofnucleotide poolsNUDT1 (MTH1)8-oxoGTPase7p22.3NM 002452DUTdUTPase15q1.1NM 001948RRM2B (p53R2)P53-inducible8q22.3NM 015713ribonucleotide reductasesmall subunit 2homologueDNA polymerases(catalytic subunits)POLBBER in nuclear DNA8p11.21NM 002690POLGBER in mitochondrial15q26.1NM 002693DNAPOLD1NER and MMR19q13.33NM 002691POLENER and MMR12q24.33NM 006231PCNASliding clamp for pol20p12.3NM 002592delta and pol epsilonREV3L (POLZ)DNA pol zeta catalytic6q231NM 002912subunit, essentialfunctionMAD2L2 (REV7)DNA pol zeta subunit1p36.22NM 006341REV1L (REV1)dCMP transferase2q11.2NM 016316POLHXP variant6p21.1NM 006502POLI (RAD30B)Lesion bypass18q21.2NM 007195POLQDNA crosslink repair3q13.33NM 006596POLK (DINB1)Lesion bypass5q13.3NM 016218POLLGap-filling during non-10q24.32NM 013274homologous end joiningPOLMGap filing during non-7p13NM 013284homologous end joiningPOLN (POL4P)DNA crosslink repair?4p16.3NM 181808Editing andProcessingnucleasesFEN1 (DNase IV)5′ nuclease11q12.2NM 004111TREX1 (DNase III)3′exonuclease, 3′3p21.31NM 033629alternative ORF of theTREX1/ATRIP geneTREX23′ exonucleaseXq28NM 007205EXO1 (HEX1)5′ exonuclease1q43NM 003686SPO11Endonuclease20q13.32NM 012444FLJ35220 (ENDOV)Incision 3′ of17q25.3NM 173627hypoxanthine and uracilRad6 pathwayUBE2A (RAD6A)Ubiquitin-conjugatingXq24-q25NM 003336enzymeUBE2B (RAD6B)Ubiquitin-conjugating5q31.1NM 003337enzymeRAD18E3 unbiquitin ligase3p25.3NM 020165UBE2V2 (MMS2)Ubiquitin-conjugating8q11.21NM 003350complexUBE2N (UBC13)Ubiquitin-conjugating12q22NM 003348complexChromatin StructureH2AFX (H2AX)Histone, phosphorylated11q23.3NM 002105after DNA damageCHAF1A (CAF1)Chromatin assembly19p13.3NM 005483factorGenes defective indiseases associatedwith sensitivity toDNA damagingagentsBLMBloom syndrome helicase15q26.1NM 000057WRNWerner syndrome8p12NM 000553helicase/3′exonucleaseRECQL4Rothmund-Thompson8q24.3NM 004260syndromeATMAtaxia telangiectasia11q22.3NM 000051Fanconi anaemiaFANCAInvolved in tolerance or16q24.3NM 000135repair of DNA crosslinksFANCBInvolved in tolerance orXp22.31NM 152633repair of DNA crosslinksFANCCInvolved in tolerance or9q22.32NM 000136repair of DNA crosslinksFANCD2Involved in tolerance or3p25.3NM 033084repair of DNA crosslinksFANCEInvolved in tolerance or6p21.31NM 021922repair of DNA crosslinksFANCFInvolved in tolerance or11p14.3NM 022725repair of DNA crosslinksFANCG (XRCC9)Involved in tolerance or9p13.3NM 004629repair of DNA crosslinksFANCLInvolved in tolerance or2p16.1NM 018062repair of DNA crosslinksFANCJ (BRIP1,BRCA1-associated DNA17q23.2NM 032043BACH1)helicaseFANCMDNA helicase and14q21.3XM 048128possible nuclease in theXPF-Hef-Mus81 familyFANCN (PALB2)PALB2 partner and16p12.1NM 024675localizer of BRCA2FAAP24 (C19orf40)Fanconi anaemia-19q13.11NM 152266associated protein, 24kDaOther identifiedGenes with asuspected DNArepair functionDCLRE1A (SNM1)DNA crosslink repair10q253.NM 014881DCLRE1B (SNM1B)Related to SNM11p13.2NM 022836RPA4Similar to RPA2Xp21.33NM 103347APTX (aprataxin)Processing of DNA9p21.1NM 175073single-strand interruptionNEIL3Resembles NEIL1 and4q34.3NM 018248NEIL3RECQL (RECQ1)DNA helicase12p12.1NM 002907RECDQL5DNA helicase17q25.1NM 00100371HEL308DNA helicase4q21.23NM 133636RAD52B (RDM1)Similar to RAD5217q12NM 145654Other conservedDNA damageresponse genesATRATM- and I-3K-like3q23NM 001184essential kinaseRAD1PCNA-like DNA damage5p13.2NM 002853sensorsRAD9APCNA-like DNA damage11q13.2NM 004854sensorsHUS1PCNA-like DNA damage7p12.3NM 004507sensorsRAD17 (RAD24)RFC-like DNA damage5q13.2NM 002873sensorCHEK1Effector kinase11q24.2NM 001274CHEK2Effector kinase22q12.1NM 007194TP53Regulation of the cell17p13.1NM 000546cycleATRIP (TREX1)ATR-interacting protein3p21.31NM 1303845′alternative ORF of theTREX1/ATRIP geneTELO2 (Hclk2,TEL2, telomere16p13.3NM 016111kiaa0683)maintenance 2, homologue